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Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy.

Fabris S, MacLean DA - PLoS ONE (2015)

Bottom Line: Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood.The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation.It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Sciences, Laurentian University, Ontario, Canada.

ABSTRACT
Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

No MeSH data available.


Doxorubicin concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.(A) * Denotes significance when compared to baseline for all muscle groups. α Indicates the highest points of accumulation of DOX (P<0.05) in the white gastrocnemius, β Indicates the highest point of accumulation (P<0.05) in the plantaris and ε Indicates the point of greatest accumulation of DOX (P<0.05) in the soleus. (B) * Denotes significance when compared to baseline for all muscle groups. α Denotes a decrease (P<0.05) compared to 48 hours in the white gastrocnemius and δ denotes a significant decrease compared to 72 hours in the red gastrocnemius. There are no significant differences between muscle types at any time point in either administered doses.
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pone.0139070.g002: Doxorubicin concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.(A) * Denotes significance when compared to baseline for all muscle groups. α Indicates the highest points of accumulation of DOX (P<0.05) in the white gastrocnemius, β Indicates the highest point of accumulation (P<0.05) in the plantaris and ε Indicates the point of greatest accumulation of DOX (P<0.05) in the soleus. (B) * Denotes significance when compared to baseline for all muscle groups. α Denotes a decrease (P<0.05) compared to 48 hours in the white gastrocnemius and δ denotes a significant decrease compared to 72 hours in the red gastrocnemius. There are no significant differences between muscle types at any time point in either administered doses.

Mentions: Following the 1.5 mg kg-1 dose, DOX was detectable in the WG at each time point (P<0.05) with the exception of 96 and 168 hours. Additionally, these concentrations were elevated (P<0.05) after 48 (0.78±0.24 μmol/kg), 72 (0.32±0.1 μmol/kg) and 120 (1.23±0.56 μmol/kg) hours post-injection (Fig 2A). The administration of 4.5 mg kg-1 dose resulted in measurable (P<0.05) DOX concentrations at each time point. When compared to 48 hours (1.62±0.61 μmol/kg), 10 and 20-fold decreases (P<0.05) were observed after 24 and 96 hours, respectively (Fig 2B).


Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy.

Fabris S, MacLean DA - PLoS ONE (2015)

Doxorubicin concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.(A) * Denotes significance when compared to baseline for all muscle groups. α Indicates the highest points of accumulation of DOX (P<0.05) in the white gastrocnemius, β Indicates the highest point of accumulation (P<0.05) in the plantaris and ε Indicates the point of greatest accumulation of DOX (P<0.05) in the soleus. (B) * Denotes significance when compared to baseline for all muscle groups. α Denotes a decrease (P<0.05) compared to 48 hours in the white gastrocnemius and δ denotes a significant decrease compared to 72 hours in the red gastrocnemius. There are no significant differences between muscle types at any time point in either administered doses.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581622&req=5

pone.0139070.g002: Doxorubicin concentrations in skeletal muscle groups following the IP administration of (A) 1.5 mg kg-1 or (B) 4.5 mg kg-1 of Doxorubicin.(A) * Denotes significance when compared to baseline for all muscle groups. α Indicates the highest points of accumulation of DOX (P<0.05) in the white gastrocnemius, β Indicates the highest point of accumulation (P<0.05) in the plantaris and ε Indicates the point of greatest accumulation of DOX (P<0.05) in the soleus. (B) * Denotes significance when compared to baseline for all muscle groups. α Denotes a decrease (P<0.05) compared to 48 hours in the white gastrocnemius and δ denotes a significant decrease compared to 72 hours in the red gastrocnemius. There are no significant differences between muscle types at any time point in either administered doses.
Mentions: Following the 1.5 mg kg-1 dose, DOX was detectable in the WG at each time point (P<0.05) with the exception of 96 and 168 hours. Additionally, these concentrations were elevated (P<0.05) after 48 (0.78±0.24 μmol/kg), 72 (0.32±0.1 μmol/kg) and 120 (1.23±0.56 μmol/kg) hours post-injection (Fig 2A). The administration of 4.5 mg kg-1 dose resulted in measurable (P<0.05) DOX concentrations at each time point. When compared to 48 hours (1.62±0.61 μmol/kg), 10 and 20-fold decreases (P<0.05) were observed after 24 and 96 hours, respectively (Fig 2B).

Bottom Line: Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood.The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation.It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Sciences, Laurentian University, Ontario, Canada.

ABSTRACT
Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.

No MeSH data available.